13-cis-Retinoic Acid Alters Intracellular Serotonin, Increases 5-HT1A Receptor, and Serotonin Reuptake Transporter Levels In Vitro

School of Human Ecology, University of Texas at Austin, Austin, Texas, United States
Experimental Biology and Medicine (Impact Factor: 2.17). 11/2007; 232(9):1195-203. DOI: 10.3181/0703-RM-83
Source: PubMed


In addition to their established role in nervous system development, vitamin A and related retinoids are emerging as regulators of adult brain function. Accutane (13-cis-retinoic acid, isotretinoin) treatment has been reported to increase depression in humans. Recently, we showed that chronic administration of 13-cis-retinoic acid (13-cis-RA) to adolescent male mice increased depression-related behaviors. Here, we have examined whether 13-cis-RA regulates components involved in serotonergic neurotransmission in vitro. We used the RN46A-B14 cell line, derived from rat embryonic raphe nuclei. This cell line synthesizes serotonin (5-hydroxytryptamine, 5-HT) and expresses the 5-HT(1A) receptor and the serotonin reuptake transporter (SERT). Cells were treated with 0, 2.5, or 10 microM 13-cis-RA for 48 or 96 hrs, and the levels of 5-HT; its metabolite, 5-hydroxyindoleacetic acid (5HIAA); 5-HT(1A) receptor; and SERT were determined. Treatment with 13-cis-RA for 96 hrs increased the intracellular levels of 5-HT and tended to increase intra-cellular 5HIAA levels. Furthermore, 48 hrs of treatment with 2.5 and 10 microM 13-cis-RA significantly increased 5-HT(1A) protein to 168.5 +/- 20.0% and 148.7 +/- 2.2% of control respectively. SERT protein levels were significantly increased to 142.5 +/- 11.1% and 119.2 +/- 3.6% of control by 48 hrs of treatment with 2.5 and 10 microM of 13-cis-RA respectively. Increases in both 5-HT(1A) receptor and SERT proteins may lead to decreased serotonin availability at synapses. Such an effect of 13-cis-RA could contribute to the increased depression-related behaviors we have shown in mice.

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Available from: Sarah J Bailey, Mar 20, 2014
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    • "The firing rate of serotoninergic neurons from the DRN can be regulated by 5-HT 1A autoreceptors, where a decrease in receptor number leads to increased basal firing activity (Richer et al., 2002) and 5- HT 1A receptor stimulation by 5-HT 1A agonists or increased intra-cellular 5-HT conversely decreases the firing activity of these neurons (Blier et al., 1998).13-Cis-RA, at 2.5 and 10 M, increased 5-HT 1A receptor and 5-HTT protein levels and intracellular 5-HT in vitro (O'Reilly et al., 2007). If these changes are recapitulated following 13-cis-RA treatment in vivo one would expect the activity of serotoninergic projections from the DRN to be diminished, potentially leading to an increase in depression-related behaviour. "
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    ABSTRACT: The synthetic retinoid 13-cis-retinoic acid (13-cis-RA), prescribed for the treatment of severe nodular acne, has been linked to an increased incidence of depression. Chronic treatment studies in rodents have shown that 13-cis-RA induces an increase in depression-related behaviours and a functional uncoupling of the hippocampus and dorsal raphe nucleus (DRN). Changes in the number of serotoninergic neurons in the DRN have been reported in depressed human patients. Given that retinoids have apoptotic effects, we hypothesized that a decrease in the number of serotoninergic neurons in the DRN or median raphe nucleus (MRN) would lead to decreased serotoninergic tone and in turn to the behavioural changes seen with 13-cis-RA administration. Here, we used immunolabelling and unbiased stereological methods to estimate the number of serotonin (5-hydroxytryptamine, 5-HT) neurons in the MRN and DRN of vehicle control and 13-cis-RA-treated adult mice. In the MRN, the number of 5-HT immunolabelled cells was 1815±194 in control, compared with 1954±111 in 13-cis-RA treated tissues. The number of 5-HT immunolabelled cells was much higher in the DRN, with 7148±377 cells in the control, compared with 7578±424 in the 13-cis-RA treated group. Further analysis of the DRN revealed that there were no changes in the number of 5-HT neurons within distinct subregions of the DRN. Similarly, changes in the density of serotoninergic neurons or in the volume of the MRN or DRN were not observed in 13-cis-RA treated animals. These data show that apoptotic actions of 13-cis-RA do not occur in vivo at drug concentrations that induce changes in depression-related behaviour and functional uncoupling of the DRN and hippocampus. The potential pro-depressant behavioural and molecular effects associated with chronic administration of 13-cis-RA may result from changes in serotoninergic activity rather than changes in the number of serotoninergic neurons.
    Neuroscience 10/2010; 172:66-73. DOI:10.1016/j.neuroscience.2010.10.050 · 3.36 Impact Factor
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    • "In 2006, O'Reilly et al. [62] showed that the chronic administration of 13-cis retinoic acid increases depression-related behaviour in mice, whereas Ferguson et al. [63], in 2007, reported that the oral treatment with 13-cis retinoic acid does not increase measures of anhedonia or depression in rats. In a more recent paper by O'Reilly et al. [64], 13-cis retinoic acid was found to increase 5-HT1A receptor and serotonin reuptake transporter levels in vitro; the authors concluded that this may lead to decreased serotonin availability at synapses. "
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    ABSTRACT: Isotretinoin, a synthetic oral retinoid that is used against severe nodulocystic acne, has been associated with various psychiatric side effects such as depression, suicidality and psychotic symptoms. A great number of reports on its effects have been published since its introduction into the market. However, a causal relationship has not been established and the link between isotretinoin use and psychiatric events remains controversial. The present paper reviews the available evidence regarding the association of isotretinoin and psychiatric side effects. All published material reporting psychiatric side effects following isotretinoin treatment, including case reports, case series, reports from adverse drug event reporting systems, prospective surveys and retrospective case-control studies, are presented. In addition, the neurobiology of the retinoids and possible biological mechanisms that may lead to psychopathology are described.
    Annals of General Psychiatry 02/2009; 8(1):2. DOI:10.1186/1744-859X-8-2 · 1.40 Impact Factor
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    ABSTRACT: Serotonin is a key neurotransmitter in the adult brain, as well as a developmental signal in the developing brain. Serotonin itself is expressed very early in both human and rodent brain, and its receptors, enzymes and transporter sites are all overdeveloped initially, peaking in some cases in the first 2 years of life and in other cases in early adolescence. In either case, the serotonin system begins to decline by early adulthood. This early peak in activity reflects the developmental function of serotonin; however, even in the adult brain, serotonin is likely to play a role in maintenance and plasticity. As a developmental signal, serotonin acts in a variety of ways, depending on the developmental stage. Earliest on, serotonin acts in an autoregulatory manner, influencing the development of its own neurons. As brain development continues, serotonin begins to act in all subsequent stages – neurogenesis/neuroprotection, gliogenesis, migration and finally differentiation and maturation. Any factor which influences the amount of serotonin during development may result in enduring changes in the brain. In this regard, concerns have been raised regarding the effects of maternal stress or drug use during pregnancy. Understanding the role of serotonin in development has made significant contributions to the study of developmental disabilities, including fetal alcohol syndrome and autism.
    Handbook of Behavioral Neuroscience
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